Vol. 282, Issue 1, 355-362, 1997

Ventilation in Morphine-Maintained Rhesus Monkeys. II: Tolerance to the Antinociceptive But Not the Ventilatory Effects of Morphine^1,2

Carol A. Paronis and James H. Woods

Departments of Pharmacology (C.A.P. and J.H.W.) and Psychology (J.H.W.), The University of Michigan Medical School, Ann Arbor, Michigan

The antinociceptive and ventilatory effects of morphine and other opioid agonists were determined in three rhesus monkeys during a period of morphine maintenance, as well as before and after the chronic exposure to morphine. Before the onset of the daily dosing regimen, morphine increased tail-withdrawal latencies from 50°C water, with an ED₅₀ of 6.4 ± 2.1 mg/kg. Daily injection of 3.2 mg/kg morphine produced a rightward displacement of the morphine dose-response curve, increasing the ED₅₀ of morphine to 28.4 ± 12.3 mg/kg. Doubling the daily morphine dose to 6.4 mg/kg resulted in a further shift to the right of the dose-response curve of morphine. After cessation of the daily dosing regimen, the morphine dose-response curve for producing antinociceptive effects returned toward baseline. The antinociceptive effects of the kappa opioid agonist, ethylketazocine, were similar during the period of daily exposure to morphine, and after cessation of the daily dosing regimen. Before the onset of the daily dosing regimen, morphine, ethylketazocine, fentanyl, butorphanol and nalbuphine decreased ventilation in the presence of air or air mixed with CO₂. The baseline ED₅₀ value of morphine for decreasing minute volume in the presence of 5% CO₂ was 2.9 ± 0.8 mg/kg. The ventilatory effects of morphine and other mu opioid agonists tested were not attenuated during the daily morphine-dosing regimen. After 40 weeks of daily injections of 3.2 mg/kg morphine, the ED₅₀ of morphine for decreasing minute volume in 5% CO₂ was 2.3 ± 1.0 mg/kg, and when the daily dose was doubled to 6.4 mg/kg morphine, the ED₅₀ of morphine was 1.5 ± 0.5 mg/kg. The ventilatory depressant effects of the daily injection 3.2 mg/kg morphine were also unchanged during morphine maintenance. The differential development of tolerance to the antinociceptive and ventilatory effects of morphine demonstrates a separation of these two mu opioid agonist effects in rhesus monkeys.